According to the Centers for Disease Control and Prevention, approximately one third of HIV infections in the United States have been associated with injection drug use. As combination anti-retroviral therapy has become the principal mechanism for HIV treatment, it is important to understand the potential interactions of drugs and immune reconstitution during anti-retroviral therapy. In general, roughly 20% of HIV-infected persons may experience poor CD4+ T cell reconstitution after initiation of anti-retroviral therapy despite sustained virologic control. Although the reasons for poor immune restoration during anti-retroviral therapy may be complex, there exists an inverse association with immune activation. Recent studies suggest that immune activation may be the consequence of increased gut permeability and exposure to microbial products that occurs with HIV infection. The first aim of the proposed studies combines measures of immune activation and microbial translocation with sophisticated proteomics analyses of plasma and central memory T cells in HIV-infected persons who experience good or poor immunologic recovery while receiving anti-retroviral therapy. The overall goal is to utilize proteomics to uncover mechanistic insights and to identify important clinical markers of immune activation and CD4+ T cell reconstitution among HIV-infected persons receiving anti-retroviral therapy. The second aim of these studies focuses on a direct proteomics comparison between HIV-infected persons receiving methadone treatment and clinically matched controls. Thus, the results of the 1st study will provide protein expression patterns with biological implications for CD4+ T cell reconstitution, while the second aim will investigate the influence of opioid exposure on these protein expression patterns. Overall, these pilot studies will provide the foundation for targeted hypotheses that explore the interplay between opioid exposure, immune activation and T cell reconstitution in HIV disease.